VYNE Therapeutics Inc. announced preclinical data showing that its pan-bromodomain and extra-terminal (?BET?) inhibitor, VYN201, significantly reduced the expression of several key pro-inflammatory cytokines relevant to Th17-mediated autoimmune diseases in an animal model and an ex vivo human tissue study. The pathogenesis of many autoimmune diseases is linked to the proliferation and activity of Th17 cells, which include several diseases that VYNE is evaluating for its VYN201 program. As announced in August 2021, VYNE is focusing its R&D capabilities to advance its proprietary pipeline, featuring the BET inhibitor compounds recently licensed from In4Derm Limited. VYN201 is a first-in-class topical ?soft? pan-bromodomain BET inhibitor that is designed to control multiple pro-inflammatory pathways while mitigating systemic drug exposure. VYN201 is being developed for topical applications, potentially including rare neutrophilic dermatoses. VYNE?s proprietary formulation of VYN201 was evaluated in a well-established preclinical model in which dorsal depilated mice are topically dosed with imiquimod cream to induce a Th17 inflammation pathology over a 7-day induction phase. A further 7-day treatment phase evaluated three doses of VYN201 (0.001%, 0.01% and 0.1% concentrations) compared to a class 1 super-potent glucocorticosteroid product positive control (clobetasol propionate 0.05% cream) and vehicle control. Further, an imiquimod-naive control group (healthy control group) was included for VYN201 vehicle treatment. Key findings from the study: A dose-dependent improvement in the signs and symptoms of inflammation was observed for VYN201 treatment groups. Treatment with VYN201 0.1% resulted in a 94% reduction in the composite inflammation severity score of erythema and scaling, relative to the vehicle control group at treatment day 7. Animals treated with VYN201 0.1% experienced a reduction in inflammation comparable to those treated with the class 1 super-potent glucocorticosteroid clobetasol propionate 0.05% cream. Corresponding dose-dependent reductions were observed across all treatment groups in Th17-relevant cytokine biomarkers of inflammation, including IL-1?, IL-17, IL-6, IL-36 and TNFa for VYN201-treated animals. Treatment with VYN201 at all concentrations appeared well-tolerated based on the following observations: Animals treated with VYN201 continued to gain body weight in a similar manner to the healthy control group, whereas animals treated with clobetasol propionate cream 0.05% had a mean body weight loss of approximately 17% compared to the animals treated with VYN201 0.1%. Animals treated with VYN201 had no evidence of dermal tolerance issues, consistent with the healthy control group, whereas animals treated with clobetasol propionate 0.05% cream had significant skin atrophy as evidenced by deep wrinkling and rhytides (fine wrinkles), marked dermal translucency and loss of elasticity. An ex vivo human skin tissue study was also conducted. Human skin biopsy tissue was stimulated to induce a Th17 immuno-phenotype using a method derived from Feghali-Bostwick et al.1 In the study, the release of several key pro-inflammatory cytokines were substantially reduced when Th17-stimulated human skin tissue was treated with VYN201, resulting in greater than 95% inhibition of IL-17, IL-36 and CXCL10 release relative to vehicle control. VYN201 also demonstrated a superior anti-inflammatory effect on these cytokines when compared to the JAK1/2 inhibitor, ruxolitinib, at identical concentrations. BET proteins play a key role in regulating gene transcription via epigenetic interactions (?reading?), and recent research has determined a key role for these BET proteins in regulating B cell and T cell activation and subsequent inflammatory processes. As epigenetic readers, BET proteins regulate the recruitment of transcriptional factors that are key to the production of several pro-inflammatory cytokines. Inhibiting BET proteins blocks cytokine transcription and therefore may have significant therapeutic potential across a wide variety of immuno-inflammatory/fibrotic and myeloproliferative neoplastic disorders. A topically applied BET inhibitor product has the possibility to positively impact diseases involving multiple, diverse inflammatory cell signaling pathways that are active in rare neutrophilic dermatoses. Furthermore, bromodomain 2 selective oral BET inhibitors may present as more conveniently-administered non-biologic treatment options for both acute control and chronic management of immuno-inflammatory indications, where the damaging effects of unrestricted inflammatory signaling activity is common.